AUGUST 2019 Issue Brief Buprenorphine: An Overview for Clinicians B uprenorphine, an FDA-approved medication for addiction treatment and pain relief, cuts opioid overdose death rates in half. Yet nearly 80% of Americans RESOURCES Overcoming Common Objections to MAT (CHCF) with opioid use disorder (OUD) do not receive buprenor- Practice Guidelines phine or other medication-assisted treatment (MAT). National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use This document provides answers to frequently asked (ASAM) questions, aiming to increase prescriber comfort with Treatment Improvement Protocol 63: Clinical prescribing buprenorphine throughout the health care Guidelines for the Use of Buprenorphine in the system.* Once the basics are mastered, buprenorphine Treatment of Opioid Addiction (SAMHSA) can be as straightforward to prescribe as medications for Guidelines for the Psychosocially Assisted other medical conditions. Pharmacological Treatment of Opioid Dependence (World Health Organization) About Buprenorphine Clinical Practice Guideline for Management of Substance Use Disorder (Dept. of Veterans Affairs) Buprenorphine is one of three FDA-approved medica- tions for treatment of OUD and for acute and chronic Model Policy on DATA 2000 and Treatment of Opioid Addiction in the Medical Office (Federation of State pain; the others are methadone and long-acting nal- Medical Boards) trexone. While methadone can be administered only in highly regulated opioid treatment programs1 (OTPs), Pregnancy buprenorphine and naltrexone can be prescribed in a Medications to Treat Opioid Use During Pregnancy — wide variety of settings. An Info Sheet for Providers (SAMHSA) Health Care Settings Buprenorphine is a partial opioid agonist, meaning that $$ Rural areas and Native Americans / Alaska Natives: it acts on certain opioid receptors in the brain, providing California MAT Expansion Project potent relief from pain, cravings, and opioid withdrawal $$ Emergency departments and hospitals: symptoms, while acting as an antagonist on other opi- California Bridge Program oid receptors. Buprenorphine has a “ceiling effect” on $$ Primary care: respiration: Increasingly higher doses do not decrease Addiction Treatment Starts Here Resource Hub breathing to the same extent that other opioids do. $$ Jails and the court system: Deaths due to buprenorphine overdoses are rare and MAT in County Criminal Justice usually involve multiple medications (e.g., benzodiaz- $$ Treatment centers and SUD counselors: epines, alcohol, other opioids) or intravenous use. MAT in residential treatment * his document was originally published in 2017. It has been updated by Triveni DeFries, MD, MPH, and Scott Steiger, MD, to include more recent T evidence and practices. The information is intended to serve as a guideline, not a replacement for individual medical judgment. Stronger formulations (sublingual tablet or buccal film, governing their care delivery. The OTP setting may be injectable, or implant) are FDA-approved for OUD, while better suited to patients who have psychiatric instabil- weaker formulations are FDA-approved for pain (inject- ity, use of multiple substances, or other conditions that able, patch, and buccal film). Formulations for OUD require close monitoring. commonly include naloxone to prevent the medication from being snorted or injected. While the naloxone com- Long-acting naltrexone is a monthly injection that blocks ponent is inert and typically will not cause symptoms the effects of opioids; it has been found to be superior when used as directed, if snorted or injected, it causes to a placebo for treatment of OUD, with similar reten- severe withdrawal symptoms. Formulations for pain are tion rates compared to buprenorphine in two short-term not FDA-approved for OUD under the Drug Addiction trials.6 However, trials have been limited by high drop- Treatment Act of 2000 (DATA 2000) and should only be out rates, and the required one week of abstinence prior used for patients with a chronic pain diagnosis. to initiating naltrexone can pose a major challenge to its use. Risk of overdose after discontinuation is also a Maintenance treatment with buprenorphine decreases concern, due to loss of tolerance. Studies of naltrexone all-cause mortality by approximately 50%. Importantly, show better results in patients with strong social supports short-term buprenorphine “detox” (using medications and a high level of motivation for abstinence,7 and some to manage the brief period of acute withdrawal symp- patients prefer a nonopioid option. Oral naltrexone is toms) doubles the death rate compared to maintenance, effective for alcohol use disorder, but should not be used and methadone detox triples the death rate compared for OUD, as it was found to have a greater than threefold to maintenance.2 Patients treated with buprenorphine risk of overdose compared to buprenorphine or metha- maintenance also show improved social functioning done in Australian studies (and a greater than sevenfold compared to people receiving counseling alone (so- risk of overdose after discontinuation).8 called “detox and rehab”), with reduced criminal activity, lower rates of illicit substance abuse, and reduced risk of Buprenorphine has several advantages: It is available in HIV and hepatitis infection.3 primary care and other health care settings, it can be given to stable patients with follow-up once a month or every three months, and its partial agonist properties help pre- Buprenorphine Compared to vent overdose death. For a good review of the evidence Methadone and Naltrexone for treatment options, see the British Columbia opioid A report from the National Academies advises that pro- addiction guidelines, which recommends buprenorphine viders in any care setting should offer patients any of as first-line treatment, and methadone for patients failing the three FDA-approved treatments for OUD.4 Patients trials of buprenorphine.9 and providers may use an online decision tool published by the Substance Abuse and Mental Health Services Administration (SAMHSA) to help patients make their decision. Buprenorphine and methadone have both been proven effective in reducing all-cause mortality for patients with OUD.5 Methadone had a slightly higher retention rate in treatment both in randomized control trials and in community effectiveness studies. In the US, however, methadone maintenance treatment can only be provided by licensed OTPs, which have restrictive regulations California Health Care Foundation www.chcf.org 2 Accessibility Obstacles $$ Physical exam that is performed, referred for, or recently recorded, with attention to signs and Nearly 80% of Americans with OUD do not receive symptoms of withdrawal or intoxication treatment. Office-based treatment has increased, but availability does not meet the demand.10 Barriers to wide $$ Laboratory testing is not required, but the fol- adoption include federal training requirements (clini- lowing should be considered, initially or later in cians must obtain a DEA waiver to use buprenorphine treatment: urine drug testing, pregnancy testing, for addiction),11 lack of knowledge and training, con- liver function testing, hepatitis and HIV serologies cern about paperwork burdens and prior authorization $$ State prescription drug monitoring program data- requirements, and stigma. base (CURES in California) checked for controlled substances To overcome these obstacles, in 2015, Medi-Cal (California’s Medicaid program) removed authorization Start-Up Strategies requirements from buprenorphine sublingual and patch Strategies for starting buprenorphine (“induction”) vary formulations; in response, buprenorphine prescriptions based on the patient’s circumstances; the goal is to in Medi-Cal nearly quadrupled in four years.12 In addi- increase the patient’s chances of success with the medi- tion, the State of California launched the MAT Expansion cation by making the process as comfortable and rapid Project in 2017, providing funding and technical assis- as possible. Induction generally involves switching to tance to integrate MAT into emergency departments buprenorphine from other opioids. Several protocols are (EDs), hospitals, primary care clinics, mental health clinics, available as guides (e.g., from California Bridge14 or the jails, prisons, outpatient OTPs, syringe services organiza- Providers Clinical Support System15). tions, street medicine programs, and beyond. Buprenorphine patches can be used to alleviate with- How to Start a Patient on drawal symptoms during the transition; since patches Buprenorphine are only FDA-approved for pain, they can only be used for patients with chronic pain diagnoses (with or Initial Assessment without OUD), and not for those with only an OUD.16 See Appendix A for more detail. Standard OUD care is moving toward a “medication- first” model, where patients are started on medications Behavioral and social services are typically offered as part without extensive assessments, just as patients with of treatment. However, medications may be started prior psychosis are started on medications to stabilize them to a complete behavioral health assessment and consult, before starting behavioral health therapy. and without awaiting laboratory or urine test results, in order to lower barriers to treatment. After shared decisionmaking with the patient, a focused assessment can include the following:13 Initial Dosage $$ History that establishes diagnosis of OUD using A starting dose of buprenorphine can vary based on the DSM-5 criteria; the frequency, amount, and routes setting and circumstance, generally between 2 mg and of opioid use; and other drug or alcohol use 8  mg. Buprenorphine generally alleviates opioid with- drawal symptoms within 20 to 40 minutes after the first $$ Historyof drug treatment and discussion of dose. treatment options — that is, buprenorphine vs. methadone vs. naltrexone After the first dose, the patient should receive subse- $$ Significant medical and psychiatric history (includ- quent doses over the next 1 to 3 days, find an optimal ing suicidality), and active medication list and dose, and reach a suitable maintenance dose within 1 to allergies 2 weeks. (See the “Dosage, Duration, and Monitoring” Buprenorphine: An Overview for Clinicians www.chcf.org 3 section for more information on maintenance.) Doses for patients who have ever injected drugs, as are sterile can be titrated based on withdrawal symptoms, cravings, needles for those at risk of ongoing injection drug use. additional opioid use, and side effects (see sidebar). Blood levels stabilize in 3 to 7 days. Just as many smokers require 30 or more quit attempts before they quit for good, multiple quit attempts may be required before a patient reaches full sobriety.18 Clinicians Common Bumps in the Road should treat a return to use with compassion, as part of Nausea or headache. Dose may be too high; consider the typical course of a chronic relapsing and remitting a dose reduction trial. Taste may be causing nausea; disease. In no case should patients be dismissed from switch formulations. Inert components of the medica- treatment due to return to use or positive drug screens, tion may be the cause of nausea or headache; consider nor should they be dismissed from treatment for using switching formulation. other substances (such as THC or methamphetamine); Difficulty taking sublingually. Remind patients not to this only puts the patient at risk of overdose or other swallow but to allow the medication to fully dissolve harm. Buprenorphine is effective for OUD and should under the tongue. Films may dissolve faster; consider not be discontinued only because the patient has other switching formulations. use disorders. Returns to use or ongoing positive urine Persistent withdrawal symptoms and cravings. screens may indicate the patient needs a higher level of Explore how the patient is using the medication, pain care, and clinicians or their staff should develop relation- or other triggers, and consider a dose increase. Note ships with opioid treatment programs to facilitate these that some patients with high opioid tolerance require doses in the 16 to 24 mg range, and occasionally transfers of care. higher doses, to prevent relapse. Just as many smokers may require 30 quit Managing Withdrawal Symptoms attempts before they quit for good, Patients typically go 12 to 48 hours without other opi- multiple quit attempts may be required oids before starting buprenorphine to avoid precipitated withdrawal symptoms. The Clinical Opioid Withdrawal before a patient reaches full sobriety. Score (COWS) can help assess the patient’s withdrawal Clinicians should treat a return to drug severity.17 use with compassion, as part of the typical Medications such as nonopioid analgesics, antihis- course of a chronic relapsing and remitting tamines, anti-nausea medications, clonidine, and disease. loperamide can be provided to the patient to increase comfort during the period of withdrawal. Buprenorphine patches can be used for patients with chronic pain diag- Contraindications noses (see Appendix A). Contraindications to starting buprenorphine include a demonstrated drug allergy, or active sedation or intoxi- Harm Reduction cation. Based on a case report, the inactive naloxone Overdose prevention education and a prescription for component of combined products may build up in naloxone (in case of overdose) should be provided to all patients with moderate to severe hepatic impairment, patients considering or receiving buprenorphine, in case so buprenorphine monoproduct (without naloxone) of return to use. They should be provided again if the may be preferred in advanced cirrhosis.19 The buprenor- patient discontinues medication treatment. phine monoproduct is commonly used in pregnancy, but pregnancy is not a contraindication to the combined Lab testing for HIV and hepatitis, and immunization and product.20 There are no other absolute contraindications treatment for hepatitis A, B, and C are especially important to buprenorphine use. California Health Care Foundation www.chcf.org 4 ED and Hospital Settings Where Can a Patient Start Patients who are identified with OUD or who overdose Buprenorphine? in the ED or hospital can be started on buprenorphine Buprenorphine can be started in a wide variety of set- or methadone (see the ED-Bridge website for resources tings, including primary care clinics, specialized induction and tools). Any licensed provider in any setting, includ- clinics, at home, EDs, hospitals, correctional institutions, ing the ED, can administer buprenorphine to a patient residential facilities, OTPs, and via telehealth. Some with opioid use disorder for up to three consecutive details follow. days without a DEA waiver (administration is defined as giving a medication under observation, as opposed to Primary Care prescribing, defined as giving a prescription to be filled Primary care clinics can provide the most accessibility and at a pharmacy).24 There is no three-day limit for patients continuity for many patients. Some settings offer special- admitted to the hospital for medical conditions — they ized clinics for addiction and/or pain and for induction. can be treated with buprenorphine or methadone by Some are connected to “bridge” programs that link any licensed provider, without a DEA waiver, to prevent patients from other settings, such as emergency depart- withdrawal from complicating their medical condition.25 ments, to ongoing services.21 EDs and hospitals are increasingly recognizing their role Induction Clinics in treating the root cause of opioid-related injury and Specialized clinics devote time and staff resources to illness by starting MAT and then expediting referral to intake, assessment, evaluation of options, education, outpatient treatment. Peers or substance use treatment medication starts, and monitoring. These clinics relieve navigators can help ensure patients are linked to treat- primary care practices of the intensity and frequency of ment and recovery programs. visits associated with patients newly starting on buprenor- phine. The patients can be transferred back to primary If opioids are indicated for pain, buprenorphine can be care when they are stable on monthly prescriptions. This a safer choice for patients with active or historical sub- approach has been used successfully for over 15 years stance use, and can be administered sublingually, by in San Francisco at the Office-Based Buprenorphine patch, or by injection (intravenous or intramuscular) while Induction Clinic. A similar hub and spoke model is used in the ED. Formulations indicated for pain are weaker in Vermont and California, where complex patients go to the hub (an opioid treatment program), and stable patients are managed at the spokes (typically primary DEA Waiver Exceptions care practices).22 Clinicians do not need a DEA waiver to provide bu- prenorphine in these circumstances: Home Starts $$ When treating a patient for pain. Any formula- To increase convenience for the patient and decrease the tion — whether FDA-approved for addiction or burden on the office practice, home inductions are increas- pain — can be prescribed to any patient with a ingly common and can be offered from primary care or pain diagnosis. the ED. SAMHSA and most recent literature support $$ When treating a patient hospitalized for a either the clinic- or home-based approach.23 With a home medical condition. Both buprenorphine and start, the patient is given instructions on how to monitor methadone can be ordered to prevent withdrawal from complicating the medical condition. withdrawal symptoms and when to take the first dose (see $$ When managing withdrawal while facilitating en- examples of low-literacy patient materials in English and try into treatment. For at most three days, and as Spanish). Education, frequent office visits, and telephone long as the buprenorphine is administered (given or text outreach can maximize support for the patient dur- under observation) as opposed to prescribed. ing the transition period. Clinic-based starts or referral to Source: “Special Circumstances for Providing Buprenorphine,” opioid treatment programs could be used for those need- SAMHSA, last modified March 4, 2019, www.samhsa.gov. ing closer monitoring (e.g., psychiatric instability). Buprenorphine: An Overview for Clinicians www.chcf.org 5 than those used in addiction and are unlikely to prevent Dosage, Duration, and cravings and return to use in patients with OUD. Providers with DEA waivers can also prescribe buprenorphine to Monitoring be filled at a pharmacy and taken at home. Maintenance Dosage Correctional Facilities and The optimal dose to promote recovery and prevent Residential Treatment return to use is different for every patient and gener- Correctional facilities and residential treatment facilities also ally varies between 4 and 32  mg daily (based on the can start patients on MAT. See these resource pages about bioavailability of the commonly used buprenorphine or MAT in corrections26 and MAT in residential treatment27 buprenorphine/naloxone sublingual tablets and film). for more information and tools. Some OTPs also provide Greater rates of retention in treatment and suppression buprenorphine as an option in addition to methadone. of illicit opioid use have been found at doses of 16 mg or greater. The maximum dose is generally considered to Telehealth be 32 mg, although the FDA package insert states that Telehealth MAT is an alternative to in-person treatment doses higher than 24 mg have not been demonstrated and is growing in response to widespread demand for to have a clinical advantage in the treatment of OUD. more-convenient and private options. At the time of Some states and settings have imposed regulations on publication, the Ryan Haight Online Pharmacy Consumer the upper limit of dosing. Protection Act of 2008 requires one initial in-person visit prior to prescribing buprenorphine (and other controlled Buprenorphine can be dosed one to three times a day. substances) through telehealth, followed by another in- Because of its long-acting properties, it can also be dosed person visit every 24 months. The 21st Century Cures Act three times a week under observation. Daily dosing may of 2016 directed the FDA to amend the law to decrease enhance adherence, but taking buprenorphine every barriers to care; at the time of publication, these regula- six to eight hours provides better pain management tions had not yet been defined. In the meantime, several for patients with chronic pain. Because buprenorphine MAT telehealth companies are providing virtual individ- is a Schedule III drug, refills can be called in or faxed. ual and group services after an initial in-person visit. For Appendix B lists the formulations and dosages available. information, see Innovation Landscape: Telehealth MAT 28 and Using Telehealth to Provide Medication-Assisted Treatment in Medi-Cal  on the unique challenges and 29 Treatment Duration: opportunities in providing telehealth in California’s Detox, Maintenance, Tapering Medicaid program. Addiction specialists now consider opioid use disorder to be a chronic disease, and this perspective informs treat- ment. Although buprenorphine can be used in short-term detoxification programs, addiction experts increasingly discourage this approach and instead advise continuing buprenorphine long-term, attempting tapers only after one to two years if strongly desired by the patient and if the patient can be closely monitored for return of crav- ings or opioid use.30 Patients who stop buprenorphine during the first few months of their treatment experience high rates of return to use, even with intensive behav- ioral support.31 In a 2015 long-term treatment study, only 9% of patients remained abstinent after buprenor- phine taper, while 80% of patients reported abstinence at 18 months and 42 months if they continued daily California Health Care Foundation www.chcf.org 6 buprenorphine treatment.32 Without long-term treat- Monitoring and Diversion ment, patients often return to illicit opioid use, and if Patients should have follow-up visits that entail regular they have been abstinent for a period of time, tolerance urine drug screens including urine buprenorphine testing. to opioids is lost: the amount of drug tolerated prior to In most patients who are regularly taking buprenorphine, abstinence can be enough to cause overdose death. A the norbuprenorphine-to-buprenorphine ratio should be large meta-analysis showed that overdose death rates greater than one. If the ratio is less than one, or if no double after buprenorphine discontinuation, and they norbuprenorphine (or buprenorphine) is detected, the triple after methadone discontinuation.33 patient may not have been taking the medication regu- larly. In some cases, extremely high buprenorphine levels Detoxification and tapering with buprenorphine or indicate that patients have tampered with the urine spec- methadone is still superior to providing no medication imen. When discrepancies are found, patients should at all and can be considered in circumstances when well- be given the benefit of the doubt and approached in a informed patients specifically desire detoxification after compassionate and caring way. There may very well be counseling about risks and options. understandable explanations, and urine toxicology is only one method of treatment monitoring. The DSM-5 criteria define remission as at least 12 months without meeting criteria for OUD other than craving.34 Prescription drug monitoring programs (CURES in For patients in remission wanting to stop medications, California) should be checked regularly (California law the American Society of Addiction Medicine (ASAM) rec- requires one check for new patients and then checks ommends tapering slowly over several months. When every four months).35 Patient opioid use, cravings, and tapering, smaller doses can be used by dividing 2  mg withdrawal symptoms should be assessed. As in follow- tablets or films into smaller segments. The smallest frac- up for any chronic disease, providers should assess tion that can be realistically achieved is one-half (1 mg) medication adherence, benefits, and adverse effects. and one-quarter (0.5 mg) of a 2 mg tablet or film. Lower doses of buprenorphine approved for pain are available Buprenorphine is occasionally diverted — given or sold for patients who also have a pain diagnosis. Patients — to people who are not prescribed the medication. who are discontinuing the medication should be offered Sharing medication often occurs in areas with limited additional support, such as follow-up visits, overdose access to treatment. Strategies to address diversion can prevention counseling, and naloxone. include discussion with patients and their social supports, pill counts, shorter-duration prescriptions, urine testing, Ongoing opioid use is common in patients on main- and avoiding doses >24 mg. Both mono- and coformu- tenance treatment. Over time, opioid use typically lated (with naloxone) buprenorphine are diverted, most decreases; however, return to use may still occur and often to people actively addicted to opioids who are self- should be addressed therapeutically and not punitively. managing their withdrawal.36 Instead of discontinuing treatment when the patient returns to use, an appropriate response is to increase the ASAM has created several documents to help members dose of buprenorphine to better control cravings, while and other physicians understand best practices to pre- increasing the intensity of monitoring: either observed vent diversion: dosing in the office or at the pharmacy, or decreasing the $$ Sample Diversion Policy (PDF)37 prescribed supply. Some patients will need daily dosing, and arrangements can be made with the pharmacist to $$ Sample Treatment Agreement (PDF)38 dispense one day at a time. If the patient returns to active $$ Adherence,Diversion and Misuse of Sublingual addiction, consider the possible need for a higher level Buprenorphine (PDF)39 of care (such as an opioid treatment program). Transitions between providers and treatment settings are high risk, and efforts should be made to coordinate transitions to ensure no interruption in treatment. Buprenorphine: An Overview for Clinicians www.chcf.org 7 Substance Use Patients frequently relapsing on buprenorphine treat- Many patients with OUD have other concurrent sub- ment should be considered for a higher level of care, stance use disorders. Stabilizing OUD with medications such as at an OTP. provides the opportunity to address other substance use disorders, and each disorder merits its own treatment plan. Use of substances such as marijuana, metham- Behavioral Health Treatments phetamine, benzodiazepines, cocaine, or other drugs Many — but not all — people with OUD benefit from should not preclude treatment of OUD with buprenor- additional counseling or mental health services.46 These phine, according to ASAM.40 Some patients with multiple do not need to be provided by the prescribing pro- substance use disorders may benefit from the intensive vider. Per SAMHSA, the standard of care requires that a treatment of an OTP setting. provider be able to refer patients on buprenorphine to behavioral health treatment but does not mandate that Cannabis use has not been shown to worsen outcomes they do so, nor does it specify the type of treatment.47 for patients on buprenorphine for OUD.41 The California Patients are not required to accept referrals to behavioral Society of Addiction Medicine recommends continuing health services, and these services do not have to be buprenorphine for patients using cannabis and treating located on-site or delivered in person. Providers should patients for marijuana use disorder, if present. not hesitate to initiate and/or continue buprenorphine for patients who are not engaged in special counseling Studies have shown that patients using other drugs, like or psychosocial services.48 cocaine, have similar success with buprenorphine com- pared to patients without other drug use.42 Two studies are reassuring for communities with insuf- ficient behavioral health resources, and for patients Buprenorphine should not be withheld from patients who decline psychosocial treatment. One randomized taking benzodiazepines or other drugs that depress controlled trial showed that buprenorphine is effective the central nervous system, according to the FDA43 and even without behavioral counseling beyond the usual SAMHSA (Treatment Improvement Protocol 63: “Some care provided by good primary care providers.49 A 2016 patients may have taken appropriately prescribed ben- ASAM review found mixed support in the literature for zodiazepines for years with limited or no evidence of behavioral health interventions for opioid addiction, and misuse. For such patients, tapering benzodiazepines may it may be reasonable to consider a step-up approach, be contraindicated and unrealistic.”)44 While acknowl- with more-intensive behavioral management for the edging that use of benzodiazepines or alcohol with patients who need it.50 buprenorphine or methadone increases the risk of side effects, the FDA notes that risk of overdose is highest Buprenorphine for treatment of opioid use disorder when people are not on medications to treat OUD. Use should not be withheld from patients who do not par- of these substances should be discussed with patients, ticipate in behavioral health services. Extensive evidence and when a use disorder is present, it should be treated. demonstrates that routine visits with a medical provider doing regular medication management may be all that Loss of control is common for patients with chronic dis- some patients need to attain stability and regain control ease, whether diabetes, hypertension, or OUD. The over their lives. At the same time, many patients will be provider should address return to use as a part of the helped by supports such as motivational interviewing by treatment course. Additional counseling and support, a clinic provider, peer support groups, case management, dose adjustments, increased monitoring and frequency social supports, vocational training, counseling, and cog- of visits should be offered to patients who return to using nitive behavioral therapy. Contingency management opioids. Return to use should not be used as a basis for techniques (small incentives, such as bus passes, movie dismissal from treatment and discontinuing buprenor- tickets, or gift cards, tied to healthy behaviors) have been phine, but rather for intensification of treatment.45 consistently demonstrated to improve adherence to California Health Care Foundation www.chcf.org 8 medication and to decrease drug use. Options can be Buprenorphine can be a safer analgesic choice than offered and tailored to the individual patient.51 other opioids for: $$ Patients with severe acute pain and who have current or historical substance use disorders, Pain Management with especially in ED or hospital settings where patient Buprenorphine histories are unavailable Buprenorphine is a potent pain reliever with particular $$ Patients dependent on long-term opioids for pain, advantages for patients with chronic pain or pain compli- especially for those either experiencing negative cated by OUD. Any provider licensed by the DEA (e.g., effects from long-term opioid use or taking opi- physician, nurse practitioner, physician assistant, midwife, oids at potentially unsafe doses clinical pharmacist) can prescribe buprenorphine for pain without a DEA waiver. The DEA clarified that “limitations Unlike other long-acting opioids, buprenorphine has and requirements [relating to addiction treatment] in no relatively few drug/drug interactions and does not accu- way impact the ability of a practitioner to utilize opioids mulate in patients with renal impairment. Due to long for the treatment of pain when acting in the usual course half-life, partial agonist activity at the mu receptor, and of medical practice. Consequently, when it is necessary antagonism at the kappa receptor, common medical to discontinue a pain patient’s opioid analgesic therapy problems resulting from other long-acting opioids arise by tapering or weaning doses, there are no restrictions less frequently with buprenorphine.53 These problems with respect to the drugs that may be used. This is include sleep apnea, low testosterone, sexual dysfunc- not considered detoxification as it is applied to addic- tion, osteopenia, opioid-induced hyperalgesia, mood tion treatment.”52 If the target condition is pain, then disorders (depression and anxiety), and dysregulation of buprenorphine can be compounded by a compounding the hypothalamic pituitary adrenal axis. A growing body pharmacy to create low doses, or low doses of the buc- of literature shows improved pain relief on buprenor- cal and patch formulations can be used. For example, phine after conversion from other long-acting opioids.54 one month of each strength of the buprenorphine patch (20, 15, 10, 7.5, and then 5  mcg/hour) is one effective While some patients may be hesitant to switch to a medi- method of gradually tapering buprenorphine in a patient cation associated with addiction treatment, the potential with a pain diagnosis. Buprenorphine in formulations for for relief of the common side effects of full agonist opioids pain cannot be used for patients with addiction and with- described above can be compelling. Other patients are out a pain diagnosis due to FDA restrictions. motivated by the fact that buprenorphine is a Schedule III medication (refills can be called in) as compared to Schedule II medications. Advantages of Using Buprenorphine for Chronic Pain Buprenorphine provides excellent pain control. It has Elderly Patients with Chronic Pain an excellent safety profile due to a ceiling effect on For elderly patients using long-term opioids, transitioning respiratory suppression (meaning higher doses will to buprenorphine lowers the risk of accidental overdose not stop breathing and only rarely cause overdose). and potentially lowers the risk of medical complications Buprenorphine’s onset of action is 30 to 60 minutes, and (e.g., sleep apnea and hypogonadism). For this reason, it typically provides eight hours of pain relief, so it is usu- buprenorphine may be a safer choice for elderly patients ally given in divided doses when used for pain unless the already on daily opioid treatment. patch formulation is used. Like any opioid, buprenorphine should be used spar- ingly, and only when the benefit outweighs the risk. Buprenorphine: An Overview for Clinicians www.chcf.org 9 Treating Pain in the Emergency Prescribing Buprenorphine in Medi-Cal Department and Hospital OUD. Medi-Cal does not require prior authoriza- Buprenorphine can be effectively used for pain man- tion (Treatment Authorization Request, or TAR) when agement by ED and inpatient clinicians without a DEA prescribing buprenorphine for addiction. Prescribers waiver. Advantages of buprenorphine as a first-line opi- should include their DEA waiver number (the provider’s oid analgesic, when opioids are indicated, include lower DEA number preceded by an “x”) and “Dx: Opioid De- pendence” or “Dx: OUD” on the prescription. Pharma- abuse potential, lower risk for respiratory depression, cies should send the claim to fee-for-service Medi-Cal, longer duration of pain relief, and (for patients with OUD) not the managed Medi-Cal plan, as all buprenorphine potential lower risk of triggering return to use. As with all products are carved out from managed care. opioid analgesics, buprenorphine should be used spar- Pain. Medi-Cal does not require a TAR for the sublin- ingly for pain after both nonpharmacologic interventions gual, transdermal, and buccal buprenorphine formula- and nonopioid analgesics have failed. tions for pain; all other formulations for pain require a TAR. Prescribers should write a justification on the script about why other covered drugs are not appro- Hospitalized and Perioperative priate (e.g., inadequate response to other opioids or Patients on Buprenorphine the buprenorphine patch, or improved safety over full agonists.) The pharmacist will use this information to Discontinuing methadone or buprenorphine in the hos- complete a TAR and send it to FFS Medi-Cal for review. pital puts patients at risk for pain exacerbation, return to use, and longer lengths of stay; in addition, patients face logistical challenges starting back on buprenorphine after discontinuation.55 SAMHSA now recommends Legal and Administrative maintaining buprenorphine in the perioperative period.56 Continuing buprenorphine, with additional analgesia Facts when needed, has been shown in recent studies to be an effective way of managing inpatient and periopera- Laws Regulating Buprenorphine tive pain, and may lower length of stay compared to Prescribing buprenorphine discontinuation.57 Additional doses of The Drug Addiction Treatment Act of 2000 (DATA 2000) buprenorphine or other opioids can be given simultane- allowed physicians with eight hours of special training to ously with maintenance doses for satisfactory pain relief. prescribe buprenorphine for addiction. (Prior to that, phy- sicians were prohibited from treating opioid addition with A DEA waiver is not required to administer or dispense opioids outside of OTPs.) The Comprehensive Addiction buprenorphine or methadone for hospitalized patients and Recovery Act of 2016 allowed nurse practitioners admitted for a primary medical problem other than opi- and physician assistants to prescribe buprenorphine for oid dependency.58 addiction after completing 24 hours of certified training.59 In 2018, the Substance Use–Disorder Prevention That Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act authorized clinical nurse specialists, certified registered nurse anesthetists, and certified nurse midwives to prescribe buprenorphine as well.60 Clinicians may treat a maximum of 30 patients at a time during the first year and 100 patients per year thereafter. The patient cap can increase to 275 patients for physi- cians board-certified in addiction, or those in practices that meet certain qualifications: 24-hour call coverage, California Health Care Foundation www.chcf.org 10 use of health information technology, provision of case Medicare Part D plans are required to cover buprenor- management services, registration with the state pre- phine formulations for addiction but may require prior scription drug monitoring database, and acceptance of authorization. Information written on the prescription third-party insurance. Clinicians can submit a notifica- to justify its use will expedite the pharmacy’s ability to tion of intent to SAMHSA in order to expedite treating obtain authorization. their first patient before the DEA waiver has been fully processed. Commercial insurance plans have different rules about buprenorphine coverage for pain and addiction and may Federal regulations explicitly state that providers do not require the prescriber to contact the plan or submit an need a DEA waiver to order buprenorphine to be admin- authorization form. istered to a patient who is hospitalized, or for a patient with a pain diagnosis. The “three-day rule” also allows buprenorphine administration (not prescription) by any Documentation Required by Federal licensed provider in any setting for up to three days while and/or California Laws a patient is transitioning into ongoing treatment.61 The Chart documentation for patients on buprenorphine California Department of Public Health released a letter should explain the diagnosis and severity of opioid use in 2019 advising that no state regulations or statutes pro- disorder by DSM-5 criteria, indications and benefits of hibit this either.62 treatment, monitoring, and patient’s progress or chal- lenges in treatment. Find buprenorphine-waivered clinicians by visiting the Informed consent and treatment agreements are often SAMHSA Buprenorphine Practitioner Locator. used in practice, but they have not been studied and should not be implemented in a way that increases bar- riers to treatment (e.g., they should not be used to fire patients from care). They can be used as a tool for com- Getting Prescriptions Approved by munication and education. Health Plans Medi-Cal, California’s Medicaid program, and many other Both federal regulations (at 42 CFR Part 2) and California Medicaid and commercial health plans have removed law (Cal. Civil Code § 56.11) include restrictions on dis- prior authorization requirements for buprenorphine used closure of patient information related to substance use for addiction. Prescribers can decrease delays by writing disorder treatment that are stricter than those for other their DEA waiver number (DEA license number preceded health information. The applicability of these rules varies by “x”) and the diagnosis (e.g., opioid dependence or depending on the type of provider, whether the provider OUD) on the prescription. When prescribed for pain, it “holds themselves out” as a substance use treatment pro- is helpful to write the pain diagnosis and justification on vider, and the sources of funding. For more information, the script as well. see the California Health Care Foundation’s Fine Print: Rules for Exchanging Behavioral Health Information in Prescribers should confirm that their local pharmacy California and resources from ASAM and SAMHSA.63 stocks buprenorphine and that, in states where sub- stance use disorder treatment is carved out of managed care, the pharmacist knows the procedure for billing Medicaid. Pharmacies can be partners in addiction treat- ment by working with prescribing doctors to dispense small supplies of buprenorphine for high-risk patients and by alerting the prescriber when the patient is having difficulty, such as sedation. Buprenorphine: An Overview for Clinicians www.chcf.org 11 About the Authors Scott Steiger, MD, is an associate professor at the UCSF School of Medicine and the deputy medical director of the Opiate Treatment Outpatient Program at Zuckerberg San Francisco General Hospital. He is board certified in internal medicine and addiction medicine. Triveni DeFries, MD, MPH, is an assistant professor in internal medicine at the UCSF School of Medicine, where she completed an addiction medicine fellowship. About the Foundation The California Health Care Foundation is dedicated to advancing meaningful, measurable improvements in the way the health care delivery system provides care to the people of California, particularly those with low incomes and those whose needs are not well served by the status quo. We work to ensure that people have access to the care they need, when they need it, at a price they can afford. CHCF informs policymakers and industry leaders, invests in ideas and innovations, and connects with changemak- ers to create a more responsive, patient-centered health care system. For more information, visit www.chcf.org. California Health Care Foundation www.chcf.org 12 Appendix A. Buprenorphine Transdermal (Patch) Transition for Patients with Chronic Pain Diagnosis The following protocol was developed by Howard Kornfeld, $$ Patient on 50 mg to 100 mg methadone. Replace half MD. For more information, see “Transdermal Buprenorphine, of methadone with long-acting opioid for 3 to 4 days, Opioid Rotation to Sublingual Buprenorphine, and the then replace the other half for 3 to 4 days. Avoidance of Precipitated Withdrawal: A Review of the $$ Patient on >100 mg methadone. Replace one-quarter Literature and Demonstration in Three Chronic Pain Patients to one-half of methadone with long-acting opioid for 3 Treated with Butrans,” The Use of Transdermal Buprenorphine to 4 days and repeat in two to four steps. Patches in Aiding in Opioid Withdrawal: Clinical Effectiveness and Guidelines and “Transdermal Buprenorphine to Switch Patients from Higher Dose Methadone to Buprenorphine STEP 2. Use buprenorphine patch to transition off long- Without Severe Withdrawal Symptoms.”64 acting opioids. Prescribe the following medications: Background With changing prescribing practices, many patients taking $$ Buprenorphine patches. Use 20 mcg/hour for patients high-dose opioids for years are being tapered to lower doses or on MME ≥100, and 10 mcg/hour for patients on off opioids altogether. However, people with long-term opioid MME <100. (Patches come in 5, 10, and 20 mcg/hour; use for pain develop the same neurochemical changes seen in each box contains four patches; some pharmacists are addiction, and opioid discontinuation is poorly tolerated, espe- willing to split up boxes). cially when done abruptly. In a large review study, half of those $$ Buprenorphine sublingual 2 mg #12. The buprenor- tapered off opioids were tapered abruptly, and half of these phine mono product (without naloxone) is less were hospitalized or admitted to the ED for opioid-related expensive than the combination product, with similar diagnoses.65 efficacy; either can be used. Buprenorphine can be a safer and better-tolerated option for $$ Four days of short-acting opioid agonists. 30% to 50% patients with long-time opioid agonist use. Using buprenor- less than the current long-acting opioid dose. phine patches during induction can ease the symptoms of withdrawal during the transition. Instruct the patient to use the last long-acting opioid dose at night and place the patch in the morning. Short-acting opioids Note: This protocol is for patients with pain diagnoses (with can be used as needed before and after patch placement. or without OUD). The buprenorphine products that are FDA- approved for pain and not addiction cannot be used for STEP 3. Start sublingual buprenorphine after 3 to 4 days patients with OUD and no chronic pain diagnosis. The informa- on the patch. tion is intended to serve as a guideline, not a replacement for individual medical judgment. Note: Home starts on sublingual buprenorphine are appro- priate for stable patients with good support, when the office can be contacted for questions; otherwise, the first sublingual Buprenorphine Patch Induction buprenorphine doses should be observed in the office. STEP 1. If patient is on methadone, first transition to After 3 to 4 days, instruct the patient to take the last short-acting another opioid agonist. opioid dose at night and start 1 mg (half-tablet) in the morning. Choose an opioid agonist (morphine, oxycodone, hydromor- The patient can take another 1 mg dose later in the day. phone, hydrocodone, or oxymorphone), and calculate the morphine equivalent (online calculator).66 Due to individual Increase dose by 2 to 4 mg every 3 days, as needed to control variability, use caution when calculating the morphine equiva- pain and cravings, to a maximum of 24 mg. Unlike those with lent dose: Use 30% to 50% less than the dose calculated by OUD, many patients with chronic pain do well on lower doses. any conversion calculator, and prescribe only a small quantity of pills at a time. The slow onset of the buprenorphine delivered through the patch system should prevent precipitated withdrawal. Once $$ Patienton <50 mg methadone. Replace all metha- higher doses of sublingual buprenorphine are tolerated, dis- done with long-acting opioid for 3 to 4 days. continue the patch. Buprenorphine: An Overview for Clinicians www.chcf.org 13 Appendix B. Buprenorphine Formulations, by Type TYPE/NAME DOSAGE FORM ADULT DOSING Buprenorphine/Naloxone Buprenorphine/naloxone Sublingual film 2 mg — 0.5 mg, 4 mg — 1 mg, 8 mg — 2 mg, 12 mg — 3 mg (Suboxone, also available as generic) Buprenorphine/naloxone Buccal film 2.1 mg — 0.3 mg, 4.2 mg — 0.7 mg, 6.3 mg — 1 mg (Bunavail) Buprenorphine/naloxone Sublingual tablet 2 mg — 0.5 mg, 8 mg — 2 mg Buprenorphine/naloxone Sublingual tablet 0.7 mg — 0.18 mg, 1.4 mg — 0.36 mg, 2.9 mg — 0.71 mg, (Zubsolv) 5.7 mg — 1.4 mg, 8.6 mg — 2.1 mg, 11.4 mg — 2.9 mg Buprenorphine Monoproduct (analgesic) Buprenorphine Buccal film 75 mcg, 150 mcg, 300 mcg, 450 mcg, 600 mcg, 750 mcg, 900 mcg (Belbuca) Buprenorphine Transdermal patch, 5 mcg/hr, 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr, 20 mcg/hr (Butrans, also available as generic) extended release Buprenorphine Hydrochloride Sublingual tablet 2 mg, 8 mg (Subutex, also available as generic) Injectable/Extended Release Buprenorphine Intradermal implant 74.2 mg (Probuphine) Buprenorphine Hydrochloride Injection solution 0.3 mg/1 mL (Buprenex, also available as generic) Used for analgesia, not for OUD. Buprenorphine Subcutaneous solution 100 mg/0.5 mL, 300 mg/1.5 mL (Sublocade 100 mg, Sublocade 300 mg) Note: Buprenorphine 8 mg sublingual tablet = buprenorphine/naloxone 8 mg/2 mg sublingual film = buprenorphine/naloxone 4.2 mg/0.7 mg buccal film = buprenorphine/naloxone (Zubsolv®) 5.7 mg/1.4 mg sublingual tablet. Sources: “Buprenorphine” and “Buprenorphine Hydrochloride,” IBM Micromedex, accessed March 28, 2019, www.micromedexsolutions.com (REQUIRES LOGIN); “Buprenorphine” and “Buprenorphine and Naloxone,” Lexi-Drugs, accessed April 1, 2019, online.lexi.com (REQUIRES LOGIN); search results for “Buprenorphine,” DailyMed, Natl. Library of Medicine, n.d., dailymed.nlm.nih.gov/dailymed; and UCSF, Clinician Consultation Center, www.nccc.ucsf.edu. California Health Care Foundation www.chcf.org 14 Endnotes 1.Formerly known as methadone clinics. 10.Sarah E. Wakeman and Michael L. 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